Classification rationale

BS1BP4BP7 Likely Benign

ATM c.103C>A

NM_000051.4:c.103C>A (p.Arg35=) is a synonymous variant in exon 3 of ATM.¹ This variant is present in gnomAD v4.1 at an allele frequency of 0.00483% (78/1,613,574 alleles) with a grpmax filtering allele frequency of 0.0626% in the African/African American population, exceeding the VCEP ATM BS1 threshold of >0.05% (BS1_Strong).² SpliceAI predicts no splicing impact (max delta = 0.00), supporting a benign interpretation (BP4_Supporting).³ The variant is a synonymous substitution deep within exon 3, located 82 bases from the donor site and 30 bases from the acceptor site, well outside splice consensus regions. No aberrant splicing is predicted (BP7_Supporting).⁴ The VCEP ATM ClinGen HBOP Supplementary Table S1 (PMID 40580951) classifies this variant as Benign/Likely benign based on computational prediction, consistent with the criteria assessment.⁵ Classification: Likely Benign per VCEP ATM Rule 18 (1 Strong benign + ≥1 Supporting benign). BS1_Strong, BP4_Supporting, and BP7_Supporting are met. No pathogenic criteria are met.⁶

BS1 + BP4 + BP7 → Likely Benign

1 pvs1_variant_assessment

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

4 spliceai ↗cspec ↗

5 vcep_suppl_tables1_pmid_40580951

6 cspec ↗

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 8 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

BS1 strong Benign

VCEP ATM BS1 requires grpmax filtering allele frequency >0.05% in gnomAD v4. Observed grpmax FAF in gnomAD v4.1 is 0.00062571 (0.0626%), exceeding the 0.05% threshold. The variant is present in 78 of 1,613,574 alleles in gnomAD v4.1 with highest subpopulation frequency in African/African American (AF=0.0787%). BS1 is met at Strong strength.

gnomAD v4.1 grpmax FAF=0.00062571 (0.0626%) exceeds VCEP BS1 threshold of >0.05%. 78/1613574 alleles (AF=0.00483%)

gnomad_v4 ↗cspec ↗

✓

BP4 supporting Benign

VCEP ATM BP4 for splicing: no predicted impact via splicing (SpliceAI ≤0.1). SpliceAI max delta score is 0.00 for NM_000051.4:c.103C>A, indicating no predicted splicing alteration. The variant is deep within exon 3 (82 bases from donor site, 30 bases from acceptor site). BP4 is met at Supporting strength.

SpliceAI delta=0.00no predicted splicing impact. Synonymous variant deep in exon 3.

spliceai ↗cspec ↗

✓

BP7 supporting Benign

VCEP ATM BP7 applies to synonymous variants located further than +7 from the donor site and further than -21 from the acceptor site. NM_000051.4:c.103C>A is a synonymous variant (p.Arg35=) in exon 3 (c.73-185), positioned 82 bases upstream of the donor site and 30 bases downstream of the acceptor site, well outside the splice consensus regions. SpliceAI delta is 0.00, confirming no predicted splicing impact. BP7 is met at Supporting strength.

Synonymous variant in exon 3c.103distant from splice sites (+82 from donor

spliceai ↗cspec ↗

Assessed · not applied

Pathogenic

PS3 No experimental functional studies exist for NM_000051.4:c.103C>A.

PS4 No case-control studies identified for NM_000051.4:c.103C>A.

PM2 VCEP ATM PM2 requires gnomAD v4 frequency ≤0.001%.

PP1 No segregation data is available for NM_000051.4:c.103C>A.

PP3 VCEP ATM PP3 requires REVEL >0.733 for missense variants or SpliceAI ≥0.2 for splicing variants.

Benign

BA1 VCEP ATM BA1 requires grpmax filtering allele frequency >0.5% in gnomAD v4.

BS3 No experimental functional data demonstrating rescue of ATM-specific features or radiosensitivity exists for NM_000051.4:c.103C>A.

BP2 No evidence of co-occurrence in trans with a pathogenic variant in ATM.

N/A · 17 PVS1 · PS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.83399e-05; MAF= 0.00483%, 78/1613574 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000786918; MAF= 0.07869%, 59/74976 alleles, homozygotes = 0); grpmax FAF= 0.00062571.

v2.1

This variant is present in gnomAD v2.1 (AF= 9.908e-05; MAF= 0.00991%, 28/282600 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000884671; MAF= 0.08847%, 22/24868 alleles, homozygotes = 0); grpmax FAF= 0.00053895.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00016290182450043442, 3/18416 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0048% · 78 / 1,613,574
0 hom · FAF 0.063%

African/African American 59 / 74,976	0.079%
Admixed American 10 / 59,996	0.017%
Remaining individuals 5 / 62,478	0.008%
European (non-Finnish) 4 / 1,179,806	0.00034%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0099% · 28 / 282,600
0 hom · FAF 0.054%

African/African American 22 / 24,868	0.088%
Admixed American 5 / 35,424	0.014%
Remaining individuals 1 / 7,206	0.014%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian)

gnomAD Canada 🇨🇦

0.016% · 3 / 18,416
0 hom · FAF 0.08%

African/African American

3 / 1,020

0.29%

+ 8 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (11 clinical laboratories) and as Benign (3 clinical laboratories). (ClinVarID = 183805)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

20305132 ↗ Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. CLINVAR

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

12673804 ↗ ATM gene alterations in childhood acute lymphoblastic leukemias. CLINVAR

17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR